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Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.
- Source :
- British Journal of Cancer; 9/5/2005, Vol. 93 Issue 5, p529-537, 9p
- Publication Year :
- 2005
-
Abstract
- Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children. [ABSTRACT FROM AUTHOR]
- Subjects :
- CHILDHOOD cancer
CANCER treatment
DRUG therapy
CISPLATIN
ANTINEOPLASTIC agents
DNA repair
CANCER relapse
CLINICAL trials
COMPARATIVE studies
DRUG resistance in cancer cells
DRUG dosage
DRUG toxicity
RESEARCH methodology
MEDICAL cooperation
RESEARCH
TRANSFERASES
TUMORS
TUMOR classification
EVALUATION research
TREATMENT effectiveness
SALVAGE therapy
DACARBAZINE
Subjects
Details
- Language :
- English
- ISSN :
- 00070920
- Volume :
- 93
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- British Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 18124917
- Full Text :
- https://doi.org/10.1038/sj.bjc.6602740